Acquired Aplastic Anemia

NORD gratefully acknowledges Neal S. Young, MD, NIH/Hemalotogy Branch of the Heart Lung and Blood Institute, for his assistance in updating this report.

Synonyms of Acquired Aplastic Anemia

idiopathic aplastic anemia

immune aplastic anemia

General Discussion

Summary

Acquired aplastic anemia is a rare, serious blood disorder, due to failure of the bone marrow failure to produce blood cells. Bone marrow is the spongy substance found in the center of the bones of the body, in adults mainly the spine, pelvis, and large bones of the legs. The bone marrow contains hematopoietic stem cells. Stem cells can produce more stem cells (self-renewal) and also differentiate and proliferate, giving rise to red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells results in low levels of red and white blood cells and platelets (pancytopenia). Symptoms of aplastic anemia are those of anemia, bleeding, and infection. Although bone marrow failure can occur secondary to other disorders, most aplastic anemia is due to the immune system mistakenly targeting the bone marrow (autoimmunity). Indeed, most patients can respond to therapy that suppresses the immune system, usually ATG and cyclosporine.

Introduction

Aplastic anemia is classified as severe according to blood counts. Most of the discussion that follows relates to severe aplastic anemia. Patients with more moderately decreased blood counts; may not require treatment. Furthermore, some aplastic anemia that is genetically inherited may, first manifest in adulthood, sometimes without a family history of blood disease.

Signs & Symptoms

The symptoms of acquired aplastic anemia occur as a consequence of the bone marrow failing to produce enough blood cells. Specific symptoms vary from case to case. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to life-threatening complications.

Red and white blood cells and platelets are formed in the bone marrow. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body’s organs, white blood cells help in fighting infections, and platelets form clots to stop bleeding. A low level of circulating red blood cells is called anemia. A low level of white blood cells is known as leukopenia. A low level of platelets is known as thrombocytopenia.

Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing, and cardiac symptoms like chest pain. Individuals with leukopenia have an increase in risk of contracting bacterial and fungal infections. Individuals with thrombocytopenia are more susceptible to bruising following minimal injury and to spontaneous bleeding from the gums and nose. Women may have increased menstrual blood loss. Symptoms are dependent on the severity of the anemia, leukopenia, and thrombocytopenia.

Some individuals with acquired aplastic anemia also have another disorder at the same time, called paroxysmal nocturnal hemoglobinuria (PNH). Acquired aplastic and PNH have a close relationship that is not fully understood by researchers. It is believed that PNH arises in the setting of autoimmune acquired aplastic anemia and bone marrow failure. Individuals affected with acquired aplastic anemia are also at risk that it will evolve into another similar disorder known as myelodysplasia. In a minority of cases, acquired aplastic anemia may eventually develop leukemia. PNH is caused by an acquired genetic defect affecting the PIGA gene, limited to marrow stem cells. The PIGA gene mutations cause blood cells to become sensitive to increased destruction by complement, a blood immunity protein. About half patients with aplastic anemia have evidence of PNH at presentation, as detected by flow cytometry. Furthermore, patients who respond following immunosuppressive therapy may recover with PNH. There are a minority of MDS patients with hypoplastic or low cellularity bone marrow, as seen in acquired aplastic anemia. These conditions are often mistaken for each other, so whether one is transformed to another is uncertain. (For more information on these disorders, see the Related Disorders section of this report.)

Causes

Most cases of acquired aplastic anemia occur unrelated to any identifiable causes, or for unknown reasons (idiopathic). Researchers believe that most are due to the immune system mistakenly targeting the bone marrow (autoimmunity). Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Tests to confirm this in any individual case are not readily available, but there is much evidence to support this pathogenic mechanism.

The bone marrow contains hematopoietic stem cells. These stem cells can divide, differentiate and become red or white blood cells or platelets. In aplastic anemia, a precipitating event is hypothesized to trigger immune-mediated destruction of hematopoietic stem cells. It is believed that certain immune system cells (T-lymphocytes) target and destroy the most primitive cells capable of developing into blood cells, hematopoietic stem cells. Individuals with aplastic anemia do not have enough stem cells to produce mature blood cells. The bone marrow appears to be replaced by fat. Affected individuals eventually develop a deficiency of red and white blood cells and platelets (pancytopenia).

In the past, acquired aplastic anemia has been linked to a variety of environmental factors, especially benzene; benzene likely is directly harmful to bone marrow cells. The relationship of bone marrow failure to other chemicals, such as pesticides or insecticides, is less well established. Use of certain medical drugs, also is rarely associated with aplastic anemia, as is nonviral hepatitis. Both may trigger the immune system response that mistakenly destroys hematopoietic stem cells. However, most cases of acquired aplastic anemia have no identifiable environmental trigger.

Affected Populations

Acquired aplastic anemia affects males and females in about equal numbers. Most cases affect older children, teenagers or young adults. The incidence of aplastic anemia in Europe and Israel is two new cases among 1 million people per year. The incidence rate is two or three times greater in Asia. The exact incidence rates exist for the United States is unknown although some sources say that approximately 500-1,000 new cases of aplastic anemia are diagnosed each year.

Related Disorders

Symptoms of the following disorders can be similar to those of acquired aplastic anemia. Comparisons may be useful for a differential diagnosis:

Myelodysplastic syndromes (myelodysplasias, MDS) are a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). It is sometimes difficult to distinguish acquired aplastic anemia from MDS. In MDS, patients often suffer due to failure of the bone marrow to produce blood cell, and some MDS can develop into an acute leukemia. In MDS, there are often typical abnormalities of chromosomes of marrow cells and/or harmful mutations in specific genes present in hematopoietic stem. (For more information on this disorder, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is the premature destruction of red blood cells (hemolysis), resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich pigment of blood. Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary great and affected individuals usually do not exhibit all of the symptoms potentially associated with the disorder.

Two factors are necessary for the development of PNH: an acquired somatic (not passed on to children) mutation of the PIG-A gene, which affects hematopoietic stem cells creating defective “PNH” blood cells, and a predisposition to the multiplication and expansion of these defective stem cells. PNH arises in the setting of autoimmune bone marrow failure,. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while the healthy stem cells are destroyed, resulting in the development of PNH. (For more information on this disorder, choose “paroxysmal nocturnal hemoglobinuria” as your search term in the Rare Disease Database.)

Aplastic anemia may also occur as part of an inherited disorder such as Fanconi anemia, the telomere diseases, Schwachman-Diamond syndrome, ataxia-pancytopenia syndrome, and others.

Fanconi anemia is a rare genetic disorder that may be apparent at birth or during childhood. In some cases, Fanconi’s anemia may not be diagnosed until adulthood. Many different genes have been identified as mutated in Fanconi anemia, and they generally cells ability to repair chromosome damage, and predisposes to damage to stem cells and eventually to leukemic transformation. The disorder is characterized by deficiency of all bone marrow elements including red blood cells, white blood cells, and platelets (pancytopenia). Fanconi anemia may also be associated with heart (cardiac), kidney (renal), and/or skeletal abnormalities, as well as patchy, brown discolorations (pigmentation changes) of the skin. There are several different subtypes (complementation groups) of Fanconi’s anemia, each of which is thought to result from abnormal changes (mutations) to different genes. Each subtype appears to share the same characteristic symptoms and findings (phenotype). Fanconi’s anemia has autosomal recessive inheritance. (For more information on this disorder, choose “Fanconi Anemia” as your search term in the Rare Disease Database.)

The telomere diseases or telomeropathies can also lead to aplastic anemia. In these inherited conditions, there are inherited mutations in genes that maintain the ends of the chromosomes, called telomeres. Chromosome ends erode normally with healthy aging of cells and organisms, but attrition is accelerated in the telomere diseases. As with Fanconi anemia, patients may not show signs of disease until adulthood. In addition to bone marrow failure, telomeropathies can also lead to pulmonary fibrosis and liver cirrhosis. Family members may have different and/or multiple organs affected, and manifestations can range from mild to severe.

Diagnosis

A diagnosis of acquired aplastic anemia may be suspected when an otherwise healthy individual has low levels of all three blood cell types (pancytopenia). A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests, including a bone marrow biopsy. During this procedure, a small specimen of bone marrow tissue is surgically removed, usually from the hip or pelvis, and studied under a microscope. In acquired aplastic anemia this sample will show a dramatic reduction or complete lack of cells. Additional tests may be necessary to rule out other disorders such as leukemia and to determine if there is an inherited or genetic cause.

Standard Therapies

Treatment

Treatment of acquired aplastic anemia varies, depending upon the individual’s age, general health, and the severity of aplastic anemia. Treatment aims to correct the bone marrow failure, as well as to treat the patient’s immediate signs and symptoms. The two main forms of specific treatment are bone marrow transplantation and immunosuppressive therapies.

Initial treatment of acquired aplastic anemia may be directed toward improving the symptoms that may result from low blood counts. Such treatment consists of giving red blood cell transfusions to correct anemia, platelet transfusions to treat or prevent serious bleeding, and antibiotics to treat or prevent infections.

Bone marrow transplantation, specifically an allogeneic transplant, is the treatment of choice in children and younger adults. With allogeneic bone marrow transplant, an affected individual’s abnormal bone marrow cells are eradicated or destroyed by chemotherapy and replaced with healthy marrow obtained from a donor. The donor marrow is transplanted by injecting the cells of the donor intravenously into the patient’s body, where it travels to the patient’s bone marrow and eventually begins producing new blood cells. The best match for a bone marrow transplant is an identical twin, sibling or close relative who shares most of the same genetic makeup as the patient. However, in many cases, a search for an unrelated, matched donor is necessary, or more recently a partly matched family member is the donor.

Graft rejection and graft-versus-host disease are potential complications with any transplant procedures, including bone marrow transplant. Complications of graft-versus-host disease from a bone marrow transplant may range from mild to life threatening. Drugs may be used to prevent or treat graft rejection or graft-versus-host disease. (For more information on this disorder, choose “graft versus host disease” as your search term in the Rare Disease Database.)

Individuals who are not candidates for a bone marrow transplant, either because of advanced age or lack of a suitable donor, are usually treated with immunosuppressive treatment. In this case, drugs are used to suppress the activity of the immune system. Since many cases of acquired aplastic anemia are believed to result from an individual’s immune system mistakenly attacking bone marrow, suppressing the activity of the immune system often allows the bone marrow to recover and eventually to begin producing new blood cells. The two most commonly used immunosuppressive agents, given alone or in combination, are antithymocyte globulin (ATG) and cyclosporine. Horse ATG is more effective than rabbit ATG in the treatment of aplastic anemia.

Immunosuppressive therapy can restore an affected individual’s blood count to normal or near normal levels for prolonged periods. However, the improvement may not be permanent and the treatment must be repeated if relapses of aplastic anemia occur. In addition, individuals who successfully respond to immunosuppressive therapy are still at risk of eventually developing PNH, myelodysplasia, or leukemia.

Approximately one-third of individuals treated with immunosuppressive drugs do not respond to therapy (refractory aplastic anemia). In these cases, treatment with hematopoietic stem cell transplantation may be considered. Immunosuppression can be repeated in refractory aplastic anemia and also for patients who have relapsed.

Hematopoietic growth factors such as erythropoietin and neupogen are not effective in aplastic anemia, but surprisingly eltrombopag, a stimulator of platelet production, was effective in improving blood counts in refractory aplastic anemia. In 2014, Promacta was approved to treat patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy and are not candidates for a hematopoietic stem cell transplant. When eltrombopag was combined with standard immunosuppression as first-line therapy, response and complete response rates were higher than with immunosuppression alone.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Years Published

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